期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 48, 页码 17116-17121出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1420389111
关键词
CREB; CBP; SirT1; acetylation; phosphorylation
资金
- National Institutes of Health [R01-DK049777, R01-DK083834, R01-CA096865]
- Clayton Foundation for Medical Research
- Kieckhefer Foundation
- Leona M. and Harry B. Helmsley Charitable Trust
- NATIONAL CANCER INSTITUTE [R01CA096865] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK049777, R01DK083834, R37DK083834] Funding Source: NIH RePORTER
In the fasted state, increases in catecholamine signaling promote adipocyte function via the protein kinase A-mediated phosphorylation of cyclic AMP response element binding protein (CREB). CREB activity is further up-regulated in obesity, despite reductions in catecholamine signaling, where it contributes to the development of insulin resistance. Here we show that obesity promotes the CREB binding protein (CBP)-mediated acetylation of CREB at Lys136 in adipose. Under lean conditions, CREB acetylation was low due to an association with the energy-sensing NAD(+)-dependent deacetylase SirT1; amounts of acetylated CREB were increased in obesity, when SirT1 undergoes proteolytic degradation. Whereas CREB phosphorylation stimulated an association with the KIX domain of CBP, Lys136 acetylation triggered an interaction with the CBP bromodomain (BRD) that augmented recruitment of this coactivator to the promoter. Indeed, coincident Ser133 phosphorylation and Lys136 acetylation of CREB stimulated the formation of a ternary complex with the KIX and BRD domains of CBP by NMR analysis. As disruption of the CREB: BRD complex with a CBP-specific BRD inhibitor blocked effects of CREB acetylation on target gene expression, our results demonstrate how changes in nutrient status modulate cellular gene expression in response to hormonal signals.
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